PROJECT SUMMARY Alcohol misuse among youth and young adults is common and associated with widespread consequences at the individual and societal levels. The development of problematic alcohol use is believed to be a function of both environmental and genetic influences, with heritability estimates for alcohol use disorders (AUDs) ranging from approximately 50-60%. Incorporating genetic data into clinical studies may enhance our understanding of intervention effects by more comprehensively assessing the factors influencing risk for alcohol misuse and AUDs. The limited existing studies of gene by intervention (GxI) effects on substance use, which examine how genetics may moderate an individual's response to an intervention, have predominantly used candidate genes to measure genetic risk. Recent advances in the field of genetics allow for the estimation of variation across the genome using polygenic risk scores (PRS), which may show greater utility for understanding who benefits most from intervention. Guided by the differential susceptibility theory, we hypothesize that individuals at greater genetic risk for alcohol misuse will respond better to prevention/intervention. We also hypothesize peer deviance and drinking motives will mediate the GxI effects, such that intervention will lead to lower levels of peer deviance, drinking to cope, and drinking to enhance among those who are genetically at risk. We propose the following specific aims to address these hypotheses. We will examine whether genetic risk for alcohol misuse (measured by PRS) moderates the effectiveness of an intervention in a college sample (Aim 1a) and a youth sample (Aim 2a). We will then test whether changes in alcohol use behaviors for those at greater genetic risk are mediated by peer deviance in a college sample (Aim 1b) and youth sample (Aim 2b). Lastly, in the college sample alone, we will examine drinking motives as a mediator of GxI effects (Aim 1c). Proposed analyses capitalize on two existing datasets: Spit for Science (R37AA011408), a longitudinal study of genetic and environmental influences on substance use and emotional health in college students, in which a subset of participants (N=231) took part in online alcohol intervention, and Project Alliance (R01DA007031-A1), a community-based study in which participants took part in Family Check-Up, a strengths-based, family-centered intervention administered in middle school to promote family management and address child and adolescent adjustment problems (N=634). Using both samples will enable examination of whether GxI effects are robust and consistent across different types and developmental timings of interventions. In addition to the proposed research aims, the following training aims will support the applicant's goal to become an independent researcher leading a program of interdisciplinary research focused on improvement of clinical interventions for alcohol and substance use through the integration of genetic and biological differences. Three proposed training aims are included in this NRSA application: 1) to gain proficiency in methods for statistical genetics with focus on alcohol and substance use, 2) to broaden research experience with a range of clinical interventions for alcohol and other substance use, and 3) to develop professional skills for a career in interdisciplinary research. The proposed research bridges basic science with clinical research, and findings may contribute to our ability to integrate biology into prevention and intervention programming.